1-Substituted-6-phenyl-4H-s-triazolo{8 4,3-a{9 {8 1,4{9 benzodiazepines

ABSTRACT

6-Phenyl-4H-s-triazolo(4,3-a)(1,4)benzodiazepines of the formula (III):   wherein R is selected from the group consisting of cyano, nitro, alkylthio in which the alkyl groups are of 1 to 3 carbon atoms, inclusive, and -COOR&#39;&#39;&#39;&#39; in which R&#39;&#39;&#39;&#39; is an alkyl group defined as above; wherein R1 is selected from the group consisting of hydrogen and alkyl, defined as above, and wherein R2, R3, R4, and R5 are selected from the group consisting of hydrogen, alkyl defined as above, halogen, nitro, cyano, trifluoromethyl, and alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, and alkanoylamino, in which the carbon chain moieties are of 1 to 3 carbon atoms, inclusive, and dialkylamino in which alkyl is defined as above, are produced by condensing a 1,3-dihydro-5phenyl-2H-1,4-benzodiazepine-2-thione of the formula (I):   wherein R1, R2, R3, R4, and R5 are defined as above, with an organic acid hydrazide of the formula (II):   wherein R&#39;&#39; is selected from the groups consisting of cyano, nitro, and alkylthio in which the alkyl groups are defined as above, or by hydrolyzing a compound in which R&#39;&#39; is -CN, with an alcohol, water and hydrogen chloride to obtain a product III wherein R is -COOR&#39;&#39;&#39;&#39;, and R&#39;&#39;&#39;&#39; is alkyl, defined as above. The new products of formula III including their pharmacologically acceptable acid addition salts are useful as sedatives, tranquilizers and muscle relaxants in mammals and birds.

United States Patent [191 Hester, Jr.

[111 3,886,174 ]*May 27, 1975 1 1SUBSTITUTED-6-PHENYL-4H-S-TRIAZOLO[4,3-A][1,4]BENZODIAZEPINES [75] Inventor: Jackson B. Hester,Jr., Galesburg,

Mich.

[73] Assignee: The Upjohn Company, Kalamazoo,

Mich.

The portion of the term of this patent subsequent to Aug. 1, 1989, hasbeen disclaimed.

[22] Filed: Jan. 15, 1973 [21] Appl. No.: 323,453

Related US. Application Data Notice:

[52] US. Cl 260/308 R; 71/92; 260/239.3 D; 260/287 R; 424/269 [51] Int.Cl C07d 57/02 [58] Field of Search 260/308 R [56] References CitedUNITED STATES PATENTS 3,681,343 8/1972 Hester 260/308 R 3,734,922 5/1973Hester 260/308 R FOREIGN PATENTS OR APPLICATIONS 2,220,612 11/1972Germany 260/308 R 2,220,615 11/1972 Germany 260/308 R 7,205,705 10/1972Netherlands.... 260/208 R 2,220,716 11/1972 Germany 260/308 R 6,916,5435/1970 Netherlands 260/308 R Primary ExaminerAlton D. Rollins Attorney,Agent, or Firm-Hans L. Berneis [57] ABSTRACT6-Phenyl-4H-s-triazolo[4,3-a][ 1,4]benzodiazepines of the formula (III):

wherein R is selected from the group consisting of cyano, nitro,alkylthio in which the alkyl groups are of 1 to 3 carbon atoms,inclusive, and COOR in which R" is an alkyl group defined as above;wherein R is selected from the group consisting of hydrogen and alkyl,defined as above, and wherein R R R and R are selected from the groupconsisting of hydrogen, alkyl defined as above, halogen, nitro, cyano,trifluoromethyl, and alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,and alkanoylamino, in which the carbon chain moieties are of l to 3carbon atoms, inclusive, and dialkylamino in which alkyl is defined asabove, are produced by condensing a 1,3-dihydro-5-pheny1-2H-l,4-benzodiazepine-2-thione of the formula (I):

wherein R R R R and R are defined as above, with an organic acidhydrazide of the formula (II):

wherein R is selected from the groups consisting of cyano, nitro, andalkylthio in which the alkyl groups are defined as above, or byhydrolyzing a compound in which R is CN, with an alcohol, water andhydrogen chloride to obtain a product III wherein R is COOR", and R isalkyl,'defined as above.

The new products of formula 111 including their pharmacologicallyacceptable acid addition salts are useful as sedatives, tranquilizersand muscle relaxants in mammals and birds.

12 Claims, No Drawings 1 1-SUBSTITUTED-6-PHENYL-4H-S-TRIAZOLO [4,3- A][1,4] BENZODIAZEPINES CROSS REFERENCE TO RELATED APPLICATIONS Thisapplication is a continuation-in-part of application Ser. No. 201,207filed Nov. 22, 1971, and now abandoned, which is a continuation-in-partof application Ser. No. 138,278, filed Apr. 28, 1971, and now abandoned.

BACKGROUND OF THE INVENTION FIELD OF THE INVENTION This invention isdirected to new organic compounds and is particularly concerned withnovel l-substituted 6-phenyl-4I-I-s-triazolo[4,3-a][1,4]benzodiazepinesand a process for the production thereof.

The novel compounds and the process of production therefor can beillustratively represented as follows:

wherein R is selected from the group consisting of cyano, nitro,alkylthio in which alkyl is of l to 3 carbon atoms, inclusive; wherein Ris selected from the group consisting of hydrogen and alkyl defined, asabove, and

wherein R R R and R are selected from the group consisting of hydrogen,alkyl as defined above, halogen, nitro, cyano, trifluoromethyl, andalkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoylamino in whichthe carbon chain moieties are of l to 3 carbon atoms, inclusive anddialkylamino in which alkyl is defined as above. Compound IIla (whereinR is -CN) by hydrolysis produces compound III with R= COOR" in which R"is alkyl defined as above.

The compounds of formula III are therefore I- substituted6-phenyl-4H-s-triazolo[4,3- a] 1,4]benzodiazepines:

wherein R R R R and R have the significance of above and R has the valueof R and COOR" wherein R" is defined as above.

The more preferred species of this invention have the formula wherein Ris selected from the group consisting of cyano, nitro,

a n-ii wherein R is selected from the group consisting of cyano, nitro,

in which R is alkyl of 1 to 3 carbon atoms, inclusive, and alkylthio inwhich alkyl is defined as above; and wherein R and R are selected fromthe group consisting of hydrogen and chlorine.

The invention includes also the pharmacologically acceptable acidaddition salts of III.

The process of this invention comprises: condensing a l,3-dihydro-5-phenyl-2l-I-l ,4-benzodiazepine-2- thione of formula 1 inan organic solvent, e.g., a loweralkanol of 1 to 4 carbon atoms,inclusive, or cyclohexanol with an acid hydrazide II, at a temperaturebetween 60 and C. to give the corresponding l-substituted6-phenyl-4I-I-s-triazolo[4,3-a1][ 1,4]benzodiazepine (Illa) Thecompounds of formula Illa wherein R is cyano, can be hydrolyzed toconvert this group to a group defined as above, thereby providing acompound of formula III in which R is COOR", defined as I DE- SCRIPTIONOF THE PREFERRED EMBODIMENT Lower alkyl groups of l to 3 carbon atoms,inclusive, are exemplified by methyl, ethyl, propyl, and isopropyl.

The carbon chain moiety of alkoxy, alkylthio, alkylsulfinyl,alkylsulfonyl, dialkylamino which is of l to 3 carbon atoms, inclusive,is defined as lower-alkyl of 1 to 3 carbon atoms, inclusive, as above.

The alkanoylamino group of l to 3 carbon atoms consists of formamidoates and the like, prepared by reacting a compound of formula III withan excess of the selected pharmacologically acceptable acid.

Sedative effects of 8-chloro-6-phenyl-4H-s-triazolo- [4,3-a] l,4]benzodiazepinel-acetonitrile are shown by the following tests inmice:

Chimney test: [Med. Exp. 4 145 (1971)]: The effective intraperitonealdosage for 50 percent of the mice tested (ED is 0.3 mg./kg. The testdetermines the ability of mice to back up and out of a vertical glasscylinder within 30 seconds. At the effective dosag'e, 50 percent of themice failed doing it.

Dish test: Mice in Petri dishes cm. diameter, 5 cm. high, partiallyembedded in wood shavings), climb out in a very short time, when nottreated. Mice remaining in the dish for more than 3 minutes indicatestranquilization. ED equals the dose of test compound at which 50 percentof the mice remain in the dish. The ED (intraperitoneal administration)in this test was 0.30 mg./kg.

Pedestal test: The untreated mouse leaves the pedestal in less than aminute to climb back to the floor of the standard mouse box.Tranquilized mice will stay on the pedestal for more than 1 minute. TheED (intraperitoneal administration) is 0.7 mg./kg.

Nicotine antagonsim test: Mice in a group of 6 are injected with thetest compound 8-chloro-6-phenyl- 4Hs-triazolo[4,3 -a][l,4]benzodiazepine- 1 acetonitrile. Thirty minutes later the miceincluding control (untreated) mice are injected with nicotine salicylate(2 mg./kg.). The control mice show overstimulation, i.e., (1) runningconvulsions followed by (2) tonic extensor fits; followed by (3) death.An intraperitoneal dosage of 0.13 mg./kg. of the test compound protected50 percent of the mice against (2) and for (3) 0.15 mg./kg. (ED wasnecessary.

The pharmaceutical forms contemplated by this invention includepharmaceutical compositions suited for oral, parenteral and rectal use,e.g., tablets, powder packets, cachets, dragees, capsules, solutions,suspensions, sterile injectable forms, suppositories, bougies, and thelike. Suitable diluents or carriers such as carbohydrates (lactose),proteins, lipids, calcium phosphate, cornstrach, stearic acid,methylcellulose, and the like may be used as carriers or for coatingpurposes. Water or oil, e.g., coconut oil, sesame oil, safflower oil,cottonseed oil, peanut oil may be used for preparing solutions orsuspensions of the active drug. Sweetening, coloring and flavoringagents may be added.

For mammals and birds, food premixes, with starch, oatmeal, driedfishmeat, fishmeal flour, and the like can be prepared.

As tranquilizers, the compounds of formula III can be used in dosages of0.1 mg. to 10 mg./kg. in oral or injectable preparations as describedabove, to alleviate tension and anxiety in mammals or birds, such ase.g., occurs when animals are shipped.

Other acid addition salts of the compounds of formula III can be made,such as the fluosilicic acid adition salts which are useful mothproofingcompounds or the trichloroacetates useful as herbicides against Johnsongrass, Bermuda grass, yellow and green foxtail and quack grass.

The starting materials of formula I of this invention, substituted orunsubstituted 1,3-dihydro-5-phenyl-2H- l,4-benzodiazepine-2-thiones, aredescribed by G. A. Archer and L. H. Sternbach [J. Org. Chem. 29, 231(1964) and US. Pat. No. 3,422,091]. These compounds (I) are made by thereaction of the known substituted or unsubstitutedl,3-dihydro-5-phenyl-2H-1 ,4- benzodiazepin-Z-ones by heating withphosphorus pentasulfide in pyridine for about 45 minutes (Archer et al.,ibid.). The following compounds of formula I are representative startingmaterials:

1 ,3-dihydro-5-phenyl-2H l ,4-benzodiazepine-2- thione;

6-chloro-l ,3-dihydro-5-(m-bromophenyl)-2H-l ,4-benzodiazepine-Z-thione;

7-chloro-l ,3-dihydro-5-phenyl-2H-l ,4-benzodiazepine-2-thione;

8-chloro-l ,3-dihydro-5-phenyl-2H- l ,4-benzodiazepine-Z-thione;

7-bromo-l ,3-dihydro-5-phenyl-2H-l ,4-benzodiazepine-Z-thione;

7-chloro-l ,3-dihydro-5-(3,4-dimethy1phenyl)-2H-l ,4-

benzodiazepine-Z-thione;

l,3-dihydro-5-(2-methyl-4-methoxyphenyl)-2H- l ,4-

benzodiazepine-Z-thione;

9-bromol ,3-dihydro-5-phenyl-2H- l ,4-benzodiazepine-Z-thione;

7-methyll ,3-dihydro-5-phenyl-2l-ll ,4-benzodiazepine-2-thione;

7-nitro-l ,3-dihydro-5-phenyl-2H- l ,4-benzodiazepine- Z-thione;8-nitrol ,3-dihydro-5-(o-chlorophenyl )-2H-l ,4-benzodiazepine-Z-thione;7-bromo-l,3-dihydro-5-(o-bromophenyl)-2l-l-1,4-benzodiazepine-Z-thione;7-methylsulfinyl-l ,3-dihydro-5-(o-fiuorophenyl)-2H- l,4-benzodiazepine-2-thione; 7-methyll ,3-dihydro-5-(p-chlorophenyl)-2H-l ,4-benzodiazepine-2-thione; 7-methylthio-1,3-dihydro-5-phenyl-2l-l-l,4-benzodiazepine-Z-thione;

7-cyanol ,3-dihydro-5-( o-chlorophenyl)-2l-l-l,4-benzodiazepine-Z-thione;

3 ,6,8-trimethyll,3-dihydro-5-(m-chlorophenyl)-2l-ll,4-benzodiazepine-2-thione;

9-propylsulfonyl-7-methyl-1,3-dihydro-5-phenyl-2l-l-1,4-benzodiazepine-2-thione;

7-trifluoromethyl-1,3-dihydro-5-(o-chlorophenyl)-2H-1,4-benzodiazepine-2-thione;.

7-dimethylamin0-1,3-dihydro-5-phenyl-2H-l,4-benzodiazepine-Z-thione;

7-fluoro-1,3-dihydro-5-(o-chlorophenyl)-2H-1,4-benzodiazepine-Z-thione;

7,8-dicyano-1,3-dihydro-5-[p- (methylsulfonyl )phenyl]-2H- 1,4-benzodiazepine-2- thione; 6,9-dichloro-l ,3-dihydro-5(p-isopropylphenyl )-2l-ll,4-benzodiazepine-Z-thione;6,8-diethyl-1,3-dihydro-5-(m-ethylphenyl)-2H-1,4-

benzodiazepine-Z-thione;6-nitro-l,3-dihydro-5-(o-propylthiophenyl)-2H-1,4-

benzodiazepine-Z-thione;7,9-bix(dipropylamino)-1,3-dihydro-5-(onitrophenyl)-2H-1,4-benzodiazepine-2-thione;9-acetylamino-1,3-dihydro-5-(p-cyanophenyl)-2H-1,4-

benzodiazepine-Z-thione; and the like.

In carrying out the process of the invention, a selected1,3-dihydro-5-phenyl-2H- l ,4-benzodiazepine-2- thione (l) in an inertorganic solvent, preferably in a lower-alkanol, e.g., 1-butanol,2-butanol, hexanol, or the like is heated to between 60120 C.,preferably to the reflux temperature of the mixture, with the selectedacid hydrazide R '2 H defined as above, during 2-48 hours. In thepreferred embodiment of this invention the acid hydrazide is used inexcess such as from 2 to 5 times the theoretically required amount, butthe reaction is operative with smaller or larger amounts. The reactionperiod is between 2 and 18 hours. At the termination of the reaction,the reaction mixture can be evaporated to give a crude productconsisting of the desired6-phenyl-4H-striazolo[4,3-a][1,4]benzodiazepine llla. The crude compoundllla is then purified by standard methods, e.g. chromatography orrecrystallization from solvents such as ethyl acetate, methylenechloride, chloroform, acetonitrile, methanol, ethanol, Skellysolve Bhexanes; mixtures thereof, or the like.

6-Phenyl-4H-s-triazolo[4,3-a][ 1 ,4]benzodiazepinel-acetonitriles(compounds of formula llla in which R is C N) can be hydrolyzed in alower alkanol e.g. methanol, ethanol, propanol, or 2-propanol in thepresence of anhydrous hydrogen chloride. During the adding of hydrogenchloride cooling is necessary as the reaction is preferably carried outat 030 C. Ethyl ether may be used as a diluent in the reaction. Afterthe reaction is terminated, the reaction mixture is mixed with water,neutralized, e.g. with sodium or potassium bicarbonate, and the productrecovered by conventional methods e.g. extraction and evaporation,chromatography, recrystallization, or a combination thereof and thelike.

The following examples are illlustrative of the processes and productsof the present invention, but are not to be construed as limiting.

EXAMPLE 1 8-Chloro-6-phenyl-4H-s-triazolo[4,3- a] 1,4]benzodiazepine- 1-acetonitri1e A mixture of 1,3-dihydro-7-chloro-5-pheny1-2l-l-1,4-

benzodiazepine-Z-thione (5.72 g., 0.02 mole), cyanoacetic acid hydrazide(5.95 g., 0.06 mole) and n-butyl alcohol (275 ml.) was refluxed for 7.5hours with a slow stream of nitrogen bubbling through the mixture. Themixture was then concentrated in vacuo. The resulting residue wassuspended in water and extracted with methylene chloride. The extractwas dried and concentrated. The residue was chromatographed on silicagel (400 g.) with 2% methanol- 98% chloroform. The product eluted fromthe column was crystallized from ethyl acetate-Skellysolve B hexanes togive 2.62 g. of 8-chloro-6-phenyl-4l-l-s-triazolo[4,3-a]-[1,4]benzodiazepine-l-acetonitrile of melting point 198201 C.

Anal. calcd. for C H CI N C, 64.77; H, 3.63; CI, 10.62; N, 20.98.

Found: C, 64.52; H, 3.86; Cl, 10.51; N, 20.95.

EXAMPLE 2 8-Chloro-6-phenyl-4l-l-s4riazolo[4,3-a][ 1,4]-benzodiazepine-l-acetic acid methyl ester A stirred mixture of8-chloro-6-phenyl-4l-l-s-triazolo-[4,3-a][1,4]benzodiazepine-1.-acetonitrile (1.00 g., 0.003 mole),methanol (2 m1.) and ether (6 ml.) was cooled in a salt-ice bath andsaturated with a stream of anhydrous hydrogen chloride during 15minutes. The mixture was allowed to warm slowly to ambient temperatureand stand for 18 hours; it was then poured into water. This mixture wasneutralized with sodium bicarbonate and extracted with chloroform. Theextract was washed with brine, dried over anhydrous magnesium sulfateand then concentrated. The residue was crystallized from methanol togive (1.149 g. of a by-product of melting point 184.5-188 C. (d). Themother liquor was crystallized from methanol-ethyl acetate to give 0.126g. of a by-product, l-(aminomethyl)-7-chloro-5-phenyl-s-triazolo[4,3-a]quinoline-4-carboxylic acid methyl ester, ofmelting point 205.5207.5 C. (d). The mother liquor from thiscrystallization was concentrated and chromatographed on silica gel (50g.) with 2% methanol-98% chloroform. The first compound eluted from thecolumn was crystallized from methanol-ethyl acetate to give 0.169 g. ofmelting point 202.5-203.5 C. (d.) and 0.125 g. of melting point200.5-202.5 C. (d.) of 8-chloro-6-phenyl-4l-l-striazolo[ 4,3-a][ l,4]benzodiazepine-1-acetic acid methyl ester. The analytical sample hada melting point of 202-203 C.

Anal. calcd. for C H ClN O C, 62.21; H, 4.12; Cl, 9.67; N, 15.28.

Found: C, 62.32; H, 4.14; Cl, 10.15; N, 15.33.

EXAMPLE 3 8-Chloro-6-(o-chlorophenyl)-4H-s-triazolo-[4,3- a]1,4]benzodiazepine- 1 -acetonitrile In the manner given in Example 1,1,3-dihydro-7- chloro-5-(o-chlorophenyl)-2H-1,4-benzodiazepine-2-thione, and cyanoacetic acid hydrazide were refluxed in n-butanol togive 8-chloro-6-(o-chlorophenyl)-4H-striazolo[4,3-a]-[1,4lbenzodiazepine-l-acetonitrile.

EXAMPLE 4 8-nitro-6-phenyl-4l-l-s-triazollo[4,3-a][ 1,4]benzodiazepine-1 -acetonitrile In the manner given in Example 1, a solution of 1,3-dihydro-7-nitro-5 -phenyl-2H-1,4-benzodiazepine-2- EXAMPLE 68-Ethylthio-6-(o-chlorophenyl)-4l-I-s-triazolo-[4,3- a]l,4]benzodiazepinel -acetonitrile In the manner given in Example 1, asolution of 1,3- dihydro-7-ethylthio-5-(o-chlorophenyl)-2H-l,4-benzodiazepine-Z-thione in n-butyl alcohol was heated to 'reflux withcyanoacetic acid hydrazide to give 8- ethylthio-6-(o-chlorophenyl)-4H-s-triazolo[4,3- a][ 1,4]benzodiazepin-l-acetonitrile.

EXAMPLE 7 7-Fluoro-6-(o-bromophenyl)-4I-I-s-triazolo-[4,3- a] 1,4]benzodiazepinel -acetonitrile In the manner given in Example 1, asolution' of 1,3-dihydro-6-fluoro-5-(o-bromophenyl)-2I'I-1,4-benzodiazepine-2-thione inn-butyl alcohol was heated to reflux withcyanoacetic acid hydrazide togive 7-flu0ro- 6-(o-bromophenyl)-4H-s-triazolo[4,3-

a][ 1,4 benzodiazepinel -acetonitrile.

EXAMPLE 8 7-Trifluoromethyl-6-(p-nitrophenyl )-4H-striazolo[4,3-a][l,4]benzodiazepinel -acetonitrile In the manner given in Example I, asolution of 1,3- dihydro-6-trifluoromethyl-5-( p-nitrophenyl )-2H- 1 ,4-benzodiazepine-Z-thione in n-butyl alcohol was heated to reflux withcyanoacetic acid hydrazide to give 7- trifluoromethyl- 6-( p-nitrophenyl)-4I-l-s-triazolo[ 4 3 a] 1 ,4]benzodiazepinel -acetonitrile.

EXAMPLE 9 8-nitro-1-(nitromethyl)-6-(o-chlorophenyl)-4I-I-striazolo[4,3-a][l,4]benzodiazepine In the manner given in Example I, a solution of 1,3-dihydro-7-nitro-5-(o-chlorophenyl)-2H-l ,4-benzodiazepine-Z-thione inn-butyl alcohol was heated to reflux with nitroacetic acid hydrazide togive 8-nitro-l- (nitromethyl)-6-(o-chlorophenyl)-4I-I-s-triazolo[4,3-a][ 1 ,4]benzodiazepine.

EXAMPLE 1O In the manner given in Example 1, a solution of 1,3-dihydro-6-ethylsulfinyl-5-[p-(trifluoromethyl)phenyl]-2I-I-1,4-benzodiazepine-Z-thione in n-butyl alcohol was heated to refluxwith nitroacetic acid hydrazide to give EXAMPLE 119-Methyl-1-(nitromethyl)-6-(p-isopropylphenyl)-4H- s-triazolo[4,-3-a][l,4]benzodiazepine In the manner given in Example 1, a solution of 1,3-dihydro-8-methyl-5-(p-isopropylphenyl)-2I-I-1,4-benzodiazepine-2-thionein n-butyl alcohol was heated to reflux with nitroacetic acid hydrazideto give9-methyll-(nitromethyl)-6-(p-isopropylphenyl)-4I-I-striazolo[4,3-a][ l,4-benzodiazepine.

EXAMPLE l2 7 ,9-Diethyll -(nitromethyl)-6-( 2,4-diethylphenyl )-4I-I-s-triazolo[4,3-a] l ,4]benzodiazepine In the manner given in Example 1,a solution of 1,3- dihydro-6,8-diethyl-5-( 2,4-diethylphenyl)-2I-I- l,4-benzodiazepine-Z-thione in n-butyl alcohol was heated to reflux withnitroacetic acid hydrazide to give 7,9- diethyll -nitromethyl-6-(2,4-diethylphenyl )-4I-I-striazolo[4,3-a]-[ l,4]benzodiazepine.

EXAMPLE l3 8-Chlorol -(nitromethyl )-6-phenyl-4I-I-s-triazolo[4,3-

a][ l,4]benzodiazepine In the manner given in Example 1, 1,3-dihydro-7-chloro-5-phenyl)-2H-l,4-benzodiazepine-2-thione and nitroacetic acidhydrazide were refluxed in n-butanol to give -nitromethyl)(nitromethyl)1 6-phenyl-4H-striazolo[4,3-a][ l ,4]-benzodiazepine.

EXAMPLE l4 8-Chloro-4-methyll -(nitromethyl )-6-(pisopropylphenyl)-4I-I-s-triazolo 4,3-

a] [1 ,4]benzodiazepine In the manner given in Example I, 7-chloro-l,3-dihydro-3-methyl-5-(p-isopropylphenyl)-2H-l ,4-benzodiazepine-Z-thioneand nitroacetic acid hydrazide were refluxed in n-butanol to give8-chloro-4-methyl-1-(nitromethyl)-6-(p-isopropylphenyl)-4H-striazolo[4,3-a][ l,4]benzodiazepine.

EXAMPLE 15 8-Chlorol nitromethyl )-6-( 2,6-difluorophenyl )-4l-I-s-triazolo[4,3 -a][ l,4]benzodiazepine.

In the manner given in Example 1, 1,3-dihydro-7-chloro-5-(2,6-difluorophenyl)-2H-1,4-benzodiazepin- 2-thione andnitroacetic acid hydrazide were refluxed in n-butanol to give8-chloro-l-(nitromethyl)-6-(2,6- difluorophenyl)-4I-I-s-triazolo[4,3-

a][ l,4]benzodiazepine.

EXAMPLE 16 7,8-Dinitro-6-(2,4-dibromophenyl)-4I-I-s-triazolo[4,3- a] l,4]benzodiazepinel -acetonitrile In the manner given in Example 1, asolution of 1,3- dihydro-6,7-dintiro-5-( 2 ,4-dibromophenyl )-2I-I- l,4- benzodiazepine-Z-thione in n-butyl alcohol was heated to reflux withcyanoacetic acid hydrazide to give 7,8-

8-chloro-- dinitro-6-( 2,4-dibromophenyl ).-4H-s-triazolo[4,3- a] 1,4]benzodiazepine- 1 -acetonitrile.

EXAMPLE 1? 7-Trifluoromethyl-6-[m-(methylsulfonyl )phenyl]-4H-s-triazolo[4,3-a][ l ,4]benzodiazepine-l-acetic acid ethyl ester In themanner given in Example 2, 7-trifiuoromethyl-6-[m-(methylsulfonyl)phenyl]-4H-s-triazolo[4,3- a][l,4]benzodiazepin-l-acetonitrile was hydrolyzed in ethanol withanhydrous hydrogen chloride to give 7-trifluoromethyl-6-[m-(methylsulfonyl)phenyl]-4H-striazolo[4,3-a][1,4]benzdiazepine-l-aceticacid ethyl ester.

EXAMPLE 18 7,9-DiethyI- 6 -(2,4-diethylphenyl)-4H-s-triazolo[4,3-a][l,4]benzodiazepine-I-acetic acid propyl ester In th'e'manner given inExample 2, 7,9-diethyl-6-(2,4- diethylphenyl)-4H-s-triazolo[4,3-a][l,4]benzodiazepine-l-acetonitrile was hydrolyzed in l-propanol withanhydrous hydrogen chloride to give 7,9-diethyl-6-(2,4-diethylphenyl)-4I-I-s-triazolo[4,3-

a][ l,4]benzodiazepine-l-acetic acid propyl ester.

EXAMPLE l9 7,8-Dinitro-6-(2,4-dibromophenyl)-4I-I-s-triazolo[4,3- a][l,4]benzodiazepine-1-acetic acid methyl ester In the manner given inExample 2, 7,8dinitro-6-( 2,4- dibromophenyl)-4I-I-s-triazolo[4,3-a][l,4]benzodiazepine-lacetonitrile was hydrolyzed in methanol withanhydrous: hydrogen chloride to give 7,8-dinitro-6- (2,fidibromophenyl)-4I-I-s-triazolo[4,3-

a] lAlbenzodiazepine-l-acetic acid methyl ester.

EXAMPLE 20 8-Chloro-6-(o-chlorophenyl )-4H-s-triazolo-[ 4,3- a][I,4]benzodiazepine-l-acetic acid ethyl ester In the manner given inExample 2, 8-chloro-6-(ochlorophenyl)-4I-I-s-triazolo[4,3-a][ l,4]benzodiazepine-l-acetonitrile in ethanol-ether was treated undercooling with anhydrous hydrogen chloride to give 8-chloro-6-(o-chlorophenyl)-4Hs-triazolo[4,3-

a][ l,4]benzodiazepine-l-acetic acid ethyl ester.

EXAMPLE 21 7-Trifluoromethyl-6-(p-nitrophenyl)-4H-striazolo[4,3-a][l,4]benzodiazepine-l-acetic acid ethyl ester In the manner given inExample 2, 7-trifluoromethyl- 6-(p-nitrophenyl)-4H-s-triazolo[4,3- a] l,4]benzodiazepinel -acetonitrile' in ethanol-ether was treated undercooling with anhydrous hydrogen chloride to give7-trifluoromethyl-6-(p-nitrophenyl)- 4I-I-s-triazolo[4',3-a'][ l,4]benzodiazepinel -acetic acid ethyl ester.

EXAMPLE 22 8-Fluoro-6-(2,6-difluorophenyl)-4I-I-s-triazoIo-[4,3-a][1,4]benzodiazepine-l-acetic acid methyl ester In the manner given inExample 2, 8-fluoro-6-(2,6- difluorophenyl)-4I-I-s-triazolo[4,3-a][ 1,4benzodiazepine-l-acetonitrile in methanol-ether was treated undercooling with anhydrous hydrogen chloride to give8-fluoro-6-(2,6-difluorophenyl)-4I-I-striazolo[4,3-a][ l,4]benzodiazepine- I acetic acid methyl ester. I

EXAMPLE 23 8-Ethylthio-6-(o-chlorophenyl)-4H-s-triazolo-[4,3-a][l,4]benzodiazepine-l-acetic acid propyl ester In the manner given inExample 2, 8-ethylthio-6-(ochlorophenyl)-4H-s-triazolo[4,3-a] 1,4]benzodiazepine-l-acetonitrile in propanol-ether was treated undercooling with anhydrous hydrogen chloride to give 8-ethylthio-6-(o-chlorophenyl)-4H-striazolo[ 4,3a] l ,4]benzodiazepine- 1-acetic acid propyl ester.

EXAMPLE 24 S-Chlorol -[(methylthio)methyl]-6-(o-chlorophenyl4H-s-triazolo[4,3-a][ l,4]benzodiazepine In the mannergiven in Example1, a solution of 1,3- dihydro-7-chloro-5 o-chlorophenyl)-2I-I- 1,4-benzodiazepine-Z-thione in n-butyl alcohol was heated to reflux with(methylthio)acetic acid hydrazide to give8-chloro-1-[(methylthio)methyl]-6-(o-chlorophenyl)-4H-s-triazoIo-[4,3-a][ l ,4]benzodiazepine.

EXAMPLE 25 9-Nitrol (ethylthio)methyl]-6-[m-(propylsulfonyl)phenyl]-4H-s-triazolo[4,3-

a][ l,4]benzodiazepine In the manner given in Example I, a solution of1,3- dihydro-8-nitro-5-[m-( propylsulfonyl)phenyl]-2I-I- l ,4-benzodiazepine-Z-thione in n-butyl alcohol is heated to reflux with(ethylthio) acetic acid hydrazide to give 9-nitro-1-[(ethylthio)methyl]-6-[m-(propylsulfonyl)phenyl]-4I-I-s-triazolo[4,3-

a][ l,4]benzodiazepine.

EXAMPLE 26 EXAMPLE 278-nitro-4-methyl-1-[(isopropylthio)methyl]-6-(macetamidophenyl)-4H-s-triazolo[4,3-a] l ,4]benzodiazepine In the manner given in Example 1, 3-methyl-1,3-dihydro-7-nitro-5-( m-acetamiidophenyl )-2H- 1,4-benzodiazepine-2-thione in n-butyl alcohol was heated to reflux with(isopropylthio)acetic acid hydrazide to give 8-nitro-4-methyllisopropylthio)methyl]-6-( macetamidophenyl)-4H-s-triazolo[4,3-

a][ l ,4]benzodiazepine.

EXAMPLE 28 9-( Dimethylamino)- I -[(methylthio )methyl]-6-( 2,4-dibromopheny1)-4I-I-s-triazolo[4,3- a] l ,4]benzodiazepine In the mannergiven in Example I, 1,3-dihydro-8-(dimethylamino)-5-(2,4-dibromophenyl)-2I-I-l ,4-benzodiazepine-Z-thionein n-butyl alcohol was heated to reflux with (methylthio)acetic acidhydrazide to give 9-(dimethylamino)-l-[(methylthio)methyl]-6-(-2,4-dibromophenyl)-4H-s-triazolo-[4,3-

a][ 1,4]benzodiazepine.

EXAMPLE 29 l- Methylthio)methyl]-6-( o-chlorophenyl)-4I-I-striazolo[4,3-a][ 1,4]benzodiazepine In the manner given inExample I, l,3-dihydro--(ochlorophenyl)-2H-l,4-benzodiazepine-Z-thionein nbutyl alcohol was heated to reflux with (methylthio)aceticaicdhydrazide to give l-[(methylthio)methyl]-6-(o-chlorophenyl)-4I-I-s-triazolo[4,3-

a][ 1,4]benzodiazepine.

EXAMPLE 30 7,8-dicyanol -[(methylthio)methyl]-6-(2,4-dibromophenyl)-4I-I-s-triazolo[4,3-

a][ 1,4]benzodiazepine In themanner given in Example 1, l,3-dihydro-6,7-dicyano-5-(2,4-dibromophenyl)-2I-I-1,4-benzodiazepine-2-thione inn-butyl alcohol was heated to reflux with (methylthio)acetic acidhydrazide to give 7,8- dicyano-1-[(methylthio)methyl]-6-(2,4-dibromophenyl)-4I-I-s-triazolo-[4,3-

a] 1,4]benzodiazepine.

EXAMPLE 3 l 6-(o-chlorophenyl)-4Hs-triazolo[4,3-a][1,4]- benzodiazepinel-acetonitrile In the manner given in Example I, a solution of 1,3-dihydro5-(o-chlorophenyl )-2I-ll ,4-benzodiazepine-2- thione in n-butylalcohol was heated to reflux with cyano-acetic acid hydrazide to give6-(0- chlorophenyl)-4I-I-s-triazolo-[4,3-a][ 1,4]benzodiazepine- 1-acetonitrile.

EXAMPLE 32 8-Chloro- I -[(methylthio)methyl]-6-phenyl-4I-I-striazolo[4,3-a][ 1,4]benzodiazepine In themanner given in Example 1, a solution of 1,3-dihydro-7-chloro-5-phenyl-2I-I-l ,4-benzodiazepine-2- thione in n-butylalcohol is heated to reflux with (methylthio)acetic acid hydrazide togive 8-chloro-l- (methylthio )-methyl]-6-phenyl-4H-s-triazolo[ 4 ,3

a] l,4]benzodiazepine.

EXAMPLE 33 8-Chlorol-( nitromethyl )-6-(o-chlorophenyl)-4I-l-striazolo[4,3-a][1,4]benzodiazepine In the manner given inExample 1, a mixture of 1,3-dihydro-7-chloro-5-(o-chlorophenyl)-2I-l-1,4-benzodiazepine-Z-thione andnitroacetic acid hydrazide was refluxed in n-butanol to give 8-chloro-l-(nitromethyl)-6-(o-chlorophenyl)-4I-I-s-triazolo[4,3- a] l,4]benzodiazepine.

Pharmacologically acceptable acid addition salts are obtained fromcompounds of formula III (including IV and V) by adding from I to 3equivalents of a pharmacologically acceptable acid to a molar equivalentof the selected diazepine III (IV or V). Preferably such addition may bemade in a water-free medium e.g. ether, ethanol, or the like wherein thesalt either precipitates or is readily collected by evaporation of thesolvent.

The hydrochlorides, hydrobromides, sulfates, phosphates, acetates,tartrates, citrates, sulfamates, and the like are of particular interestin preparing pharmaceutical dosage forms.

In the manner given in the preceding examples, otherl,3-dihydro-5-phenyl-2l-l-l ,4-benzodiazepine-2- thiones of formula Ican be condensed with acid hydrazides II, as defined earlier, to giveother new I- substituted 6-phenyl-4I-I-s-triazolo[4,3-a][l,4]benzodiazepines III. Representative compounds, thus obtained,include:

lO-chloro-l-[(methylthio)methyl]-6-(m-'isopropylphenyl)-4I-I-s-triazolo[4,3 a] 1 ,4]benzodiazepine;7-(propylthio)-6-(m-trifluoromethylphenyl)-4H-striazolo-[4,3-a][1,4]benzodiazepinel -acetonitrile;8-(propionylamino)-6-(2,4-dibromophenyl)-4I-I striazolo-[4,3-a][ l,4]benzodiazepine-l-acetonit1ile;4-propyll-(nitromethyl)-6-(o-fluorophenyl)-4l l striazolo-[4,3-a][1,4]benzodiazepine; V 4-ethyll (methylthio)methyl1-6-[o- (ethylthio)phenyl]-4l-l-s-triazolo[4,3-a][l,4]benzodiazepine; i 4-methyl-7,l0-dichlorol -[(ethylthio)methyl]-6-(misopropoxyphenyl)-4I-I-s-triazolo[4,3- a][ 1,4]benzodiazepine;9-(dipropylamino)-l-[(propylthio)methyl]-6-[m-(propylthio)phenyl]-4I-I-s-triazolo[4,3- a][ 1,4]benzodiazepine; 7-(diisopropylamino)- l nitromethyl )-6-[p-(dipropylamino)-phenyl]-4I-I-s-triazolo[4,3-

a][ l,4]benzodiazepine; v g4-isopropyl-7,9-difluoro-6-phenyl-4I-I-s-triazolo[4,3 a]-[1,4]benzodiazepine-l-acetic acid ethyl ester;

8-chloro-6-(3,4-dimethylphenyl)r4I-I s-triazolo[4,3-

a][ l,4]-benzodiazepine-I acetic acid propyl ester;6-(2-methyl-4-methoxyphenyl)-4l-I-s-triazolo[4,3-

a] 1,4]-benzodiazepinel -acetonitrile;8-chloro-6-(o-chlorophenyl)-4I-l-striazolo[4,3-

a][ l,4]benzodiazepine-l-acetic acid methyl ester;6-(o-chlorophenyl)-4H-s-triazolo[4,3-

a][ 1,4]benzodiazepin- 1 -acetic acid methyl ster;6-phenyl-4H-s-triazolo[4,3-a][ 1,4]benzodiazpinel acetic acid methylester; l 8-chloro-6-phenyl-4I-I-s-triazolo[4,3-

a][ l,4]benzodiazepin-l-acetic acid ethyl ester;

6-(o-chlorophenyl)-4I-I-s-triazol0[4,3-

a][l,4]benzodiazepin-l-acetic acid ethyl ester;6-phenyl-4I-I-s-triazolo[4,3-a][ 1,4]benzodiazepin- 1 acetic acid ethylester;8fluoro-6-(o-chlorophenyl)-l-(nitromethyl)-4I-I-striazolo-[4,3-a][1,4]benzodiazepine;6-(o-chlorophenyl)- 1-(nitromethyl)-4I-I-s-triazolo[4,3-

a]-[ 1,4]benzodiazepine, 6-phenyl- 1 -(nitromethyl)-4I-I-s-triazolo[4,3-

a][ 1,4]benzodiazepine; 8-Nitrol(methylthio)methyl']-6-phenyl-4I-I-striazolo-[4,3-a][1,4]benzodiazepine; l-[ (methylthio )meth'yl]6-phenyl-4I-I-s-triazolo[ 4,3-

a][ l,4]-benzodia zpine';8-(trifluoromethyl)-l-[(methylthio)methyl]-6-phenyl-4I-I-s-triazolo[4,3-a][ l',4]benzodiazepine;8-(methylthio)-l-[(methylthio)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine; t 8-( methylthio l nitromethyl)6-phenyl-4I-l-striazolo-[4,3-a][1,4]benzodiazepine;

6-phenyl-4H-s-triazolo[4,3-a][ 1,4]benzodiazepinel acetonitrile;

8-nitro-6-phenyl-4H-s-triazolo[4,3-a][ 1,4]benzodiazepine-l-acetic acidmethyl ester;

and the like.

I claim:

1. A l-substituted 6-phenyl-4l-l-s-triazolo[4,3- a][ l,4]-benzodiazepineof the formula (III):

wherein R is selected from the group consisting of cyano, nitro,alkylthio in which the alkyl moiety is of l to 3 carbon atoms,inclusive, and COOR" in which R" is alkyl defined as above; wherein R,is selected from the group consisting of hydrogen and alkyl, defined asabove; and wherein R R R and R are selected from the group consisting ofhydrogen, alkyl of l to 3 carbon atoms, inclusive, halogen, nitro,cyano, trifluoromethyl, and alkoxy, alkylthio, alkylsulfiny],alkylsulfonyl, alkanoylamino in which the carbon chain moieties are of lto 3 carbon atoms, inclusive, and dialkylamino in which alkyl is definedas above, and the pharmacologically acceptable acid addition saltsthereof.

2. A compound according to claim 1 of the formula IV:

wherein R is selected from the group consisting of cyano, nitro,

in which R" is alkyl of l to 3 carbon atoms, inclusive, and alkylthio inwhich alkyl is as defined above; wherein R and R are selected from thegroup consisting of hydrogen, fluorine, chlorine, bromine, and nitro;and wherein R is selected from the group consisting of hydrogen,fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl, andalkylthio in which alkyl is defined as above, and the pharmacologicallyacceptable acid addition salts thereof.

3. A compound according to claim 1 of the formula V wherein R isselected from the group consisting of cyano, nitro,

in which R" is alkyl of l to 3 carbon atoms, inclusive and alkylthio inwhich alkyl is as defined above; and wherein R and R are selected fromthe group consisting of hydrogen and chlorine.

4. The compound according to claim 1, wherein R is in which R" is alkylof l to 3 carbon atoms, inclusive.

5. The compound of claim 3, wherein R is COOCH R is hydrogen and R ischloro and the compound is therefore8-chloro-6-phenyl-4H-striazolo[4,3-a] l ,4]benzodiazepinel -acetic acidmethyl ester.

6. A compound according to claim 3, wherein R is COOC H R and R arechloro, and the compound is8-chloro-6-(o-chlorophenyl)-4l-I-s-triazolo[4,3- a][l,4]-benzodiazepin-l-acetic acid ethyl ester.

7. The compound of claim 3, wherein R is -CN, R is hydrogen and R ischloro, and the compound is therefore8-chloro-6-phenyl-4H-s-triazolo[4,3- a][ 1,4]benzodiazepine-1-acetonitrile.

8. A compound according; to claim 3, wherein R is CN, R and R are chloroand the compound is therefore8-chloro-6-(o-chlorophenyl)-4H-s-triazolo[4,3- a] l ,4]benzodiazepinl-acetonitrile.

9. A compound according to claim 3 wherein R is methylthio, R ishydrogen, R is chloro and the compound is therefore8-chloro-l-[(methylthio)methyl]-6- phenyl-4H-s-triazolo[4,3-a][ l,4]benzodiazepine.

10. A compound according to claim 3 wherein R is methylthio, R and R arechloro and the compound is therefore8-chloro-l-[(methylthio)methyl]-6-(ochlorophenyl)-4H-s-triazolo[4,3-

a] l ,4]benzodiazepine.

11. A compound according to claim 3 wherein R is v nitro, R9 ishydrogen, R10 is chloro and the compound is thereforeS-chloro-1-(nitromethyl)-6-phenyl-4H-striazolo-[4,3-a] [l,4]benzodiazepine.

12. A compound according to claim 3 wherein R is nitro, R and R arechloro and the compound is therefore 8 -ch1orol-(nitromethyl)-6-(o-chlorophenyl)-4H- s-triazolo[4,3-a][1,4]benzodiazepine.

1. A 1-SUBSTITUTED 6-PHENYL-4H-S-TRIAZOLO(4,3-A)(1,4)BENZODIAZEPINE OFTHE FORMULA (III)-
 2. A compound according to claim 1 of the formula IV:3. A compound according to claim 1 of the formula V
 4. The compoundaccording to claim 1, wherein R is
 5. The compound of claim 3, wherein Ris -COOCH3 R9 is hydrogen and R10 is chloro and the compound istherefore8-chloro-6-phenyl-4H-s-triazolo(4,3-a)(1,4)benzodiazepine-1-acetic acidmethyl ester.
 6. A compound according to claim 3, wherein R is -COOC2H5,R9 and R10 are chloro, and the compound is8-chloro-6-(o-chlorophenyl)-4H-s-triazolo(4,3-a)(1,4)-benzodiazepin-1-aceticacid ethyl ester.
 7. The compound of claim 3, wherein R is -CN, R9 ishydrogen and R10 is chloro, and the compound is therefore8-chloro-6-phenyl-4H-s-triazolo(4,3-a)(1,4)benzodiazepine-1-acetonitrile.8. A compound according to claim 3, wherein R is CN, R9 and R10 arechloro and the compound is therefore8-chloro-6-(o-chlorophenyl)-4H-s-triazolo(4,3-a)(1,4)benzodiazepin-1-acetonitrile.
 9. A compound according to claim 3 wherein R ismethylthio, R9 is hydrogen, R10 is chloro and the compound is therefore8-chloro-1-((methylthio)methyl)-6-phenyl-4H-s-triazolo(4,3-a)(1,4)benzodiazepine.
 10. A compound according to claim 3 wherein R ismethylthio, R9 and R10 are chloro and the compound is therefore8-chloro-1-((methylthio)methyl)-6-(o-chlorophenyl)-4H-s-triazolo(4,3-a)(1,4)benzodiazepine.
 11. A compound according to claim 3 wherein R isnitro, R9 is hydrogen, R10 is chloro and the compound is therefore8-chloro-1-(nitromethyl)-6-phenyl-4H-s-triazolo-(4,3-a)(1,4)benzodiazepine.12. A compound according to claim 3 wherein R is nitro, R9 and R10 arechloro and the compound is therefore 8-chloro-1-(nitromethyl)-6-(o-chlorophenyl)-4H-s-triazolo(4,3-a)(1,4)benzodiazepine.